The invention relates to a process and apparatus for the continuous making of DL-.alpha.-hydroxy-.beta.,.beta.-dimethyl-.gamma.-butyrolactone (DL-pantolactone).
Pantolactone is of importance as one of the starting materials for the synthesis of DL-pantothenic acid, DL-Ca-pantothenate and pantothenylol (panthenol) as well as D(+)-pantothenic acid, D(+)-Ca-pantothenate and D(+)-pantothenylol. All these products have therapeutical value as vitamins.
Ordinarily DL-pantolactone is made in the following manner. Isobutyraldehyde is condensed with formaldehyde in the presence of an alkaline catalyst so as to form formisobutyraldol. The formisobutyraldol cyanohydrine which is obtained by the addition reaction between hydrocyanic acid and formisobutyraldol is then further hydrolyzed by heating with a mineral acid so as to form .alpha., .gamma.-dihydroxy-.beta.,.beta.-dimethylbutyric acid. The latter product can be converted by further heating with mineral acid without difficulty to the DL-pantolactone.
As a catalyst for making the formisobutyraldol potassium carbonate has been used. It has furthermore been found that the aldol condensation can also be catalyzed with alkali cyanides. This approach has been preferred because the next step thereafter is the addition reaction with hydrocyanic acid. The process is generally carried out at a temperature between 0.degree. C. and 30.degree. C. The reaction mass is usually left standing for a few hours.
Occasionally sodium bisulfite has been added in order to obtain the formisobutyraldol-bisulfite compound. Thus there were released only equivalent amounts of hydrocyanic acid from the added potassium cyanide. In another synthesis the formisobutyraldol and sodium cyanide containing reaction mass was neutralized with mineral acids and the required amount of hydrocyanic acid was thus released. The residence time in this case was between 5 and 15 hours.
In some processes the formed cyanohydrin was isolated by extraction with ether. However, normally the cyanohydrin was hydrolyzed without isolation by heating with concentrated or fuming hydrochloric acid to form .alpha.,.gamma.-dihydroxy-.beta.,.beta.-dimethylbutyric acid which simultaneously was lactonized to the DL-pantolactone. In order to isolate the DL-pantolactone the reaction mass is then subjected to evaporation to dryness and the residue is extracted with acetone.
In another method the reaction mass was extracted directly with methylenechloride, ethylenechloride, ether or amylenehydrate. The crude DL-pantolactone thus obtained was recrystallized either from ether/petrol ether or was subjected to distillation in a vacuum.
In another prior art process the approach was this: A true solution made from isobutyraldehyde and formalin upon addition of methanol is added to an aqueous sodium cyanide solution and precautions are taken that the temperature in the reaction mixture does not exceed 20.degree. C. The mixture is then permitted to stand for 2 hours. Subsequently it is neutralized with mineral acid and then further hydrolyzed to the .alpha.,.gamma.-dihydroxy-.beta.,.beta.-dimethylbutyric acid and lactonized to DL-pantolactone by heating for 1 hr. at reflux temperature. The thus obtained DL-pantolactone is extracted by means of methylene chloride from the mixture and after evaporation of the solvent is converted with sodium hydroxide to sodium pantoate. The yield in this case is 62.3% of pure DL-pantolactone relative to the initial isobutyraldehyde.
Still another process proceeds by adding 37% formalin and methanol to an aqueous potassium carbonate solution and reacting the mixture dropwise at 25.degree. C. with isobutyraldehyde and then stirring the mixture for 2 hr. at 25.degree. C. and for 1 hr. at 35.degree. C. The formisobutyraldol containing solution is then reacted during a period of 1 hr. at 5.degree. to 10.degree. C. in the presence of a CaCl.sub.2 solution with a sodium cyanide solution and after stirring for 3 hrs. is neutralized with concentrated hydrochloric acid, hydrolyzed and lactonized to the DL-pantolactone. In this process a yield of 86% is obtained.
All these prior art processes have various shortcomings. The use of potassium carbonate for the separate condensation to formisobutyraldol increases the cost. Furthermore the isolation of formisobutyraldol and the making of the aldehyde-bisulfite compound do not result in any particular benefit. The long reaction time, and this includes the standing period on the shelf and the time for cooling the reaction mixture, which is necessary in the various stages of DL-pantolactone synthesis is the result of the discontinuous operation and is typical of all prior art processes. The practical performance of the synthesis thus becomes inconvenient and costly. The addition of CaCl.sub.2 solution results in a higher yield of DL-pantolactone. However the shortcomings of the long reaction times apply also to this process. This process furthermore involves difficulties because of the formation of suspensions. Therefore, the present invention therefore has the object to provide for a continuous operation in order to obtain high yields of DL-pantolactone at a high performance rate per hour without having to cope with the above-listed difficulties.